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• W2085453879 abstract "HomeCirculationVol. 122, No. 21Lipoprotein-Associated and Secreted Phospholipases A2 in Cardiovascular Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBLipoprotein-Associated and Secreted Phospholipases A2 in Cardiovascular DiseaseRoles as Biological Effectors and Biomarkers Ziad Mallat, MD, PhD, Gérard Lambeau, PhD and Alain Tedgui, PhD Ziad MallatZiad Mallat From the Institut National de la Santé et de la Recherche Médicale (INSERM), U970, Paris-Cardiovascular Research Center, and Université Paris Descartes, UMR-S970 (Z.M., A.T.), Paris, France; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital (Z.M.), Cambridge, United Kingdom; and Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR 6097, Université de Nice Sophia-Antipolis (G.L.), Valbonne, France. Search for more papers by this author , Gérard LambeauGérard Lambeau From the Institut National de la Santé et de la Recherche Médicale (INSERM), U970, Paris-Cardiovascular Research Center, and Université Paris Descartes, UMR-S970 (Z.M., A.T.), Paris, France; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital (Z.M.), Cambridge, United Kingdom; and Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR 6097, Université de Nice Sophia-Antipolis (G.L.), Valbonne, France. Search for more papers by this author and Alain TedguiAlain Tedgui From the Institut National de la Santé et de la Recherche Médicale (INSERM), U970, Paris-Cardiovascular Research Center, and Université Paris Descartes, UMR-S970 (Z.M., A.T.), Paris, France; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital (Z.M.), Cambridge, United Kingdom; and Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique UMR 6097, Université de Nice Sophia-Antipolis (G.L.), Valbonne, France. Search for more papers by this author Originally published23 Nov 2010https://doi.org/10.1161/CIRCULATIONAHA.110.936393Circulation. 2010;122:2183–2200Phospholipases A2 (PLA2s) belong to a superfamily of enzymes that catalyze the hydrolysis of glycerophospholipids at the sn-2 position, producing nonesterified fatty acids, such as arachidonic acid, and lysophospholipids.1,2 In many cases, the PLA2 lipid products lead to the generation of a variety of downstream signaling molecules, including prostaglandins, leukotrienes, lysophospholipids, platelet-activating factor (PAF), and oxidized lipids, that induce a multitude of biological actions in virtually all tissues, including the cardiovascular system.3–8 PLA2s comprise distinct sets of enzymes with different localizations: 1 cytosolic enzymes that are Ca2+-dependent (cPLA2), Ca2+-independent (iPLA2), or specific for PAF (intracellular PAF-acetylhydrolase); and 2 extracellular enzymes, either associated with lipoproteins (Lp-PLA2, also known as the secreted PAF acetylhydrolase) or typically secreted (sPLA2) and present in the extracellular space. The cPLA2 family consists of 6 enzymes, among which the cytosolic Ca2+-dependent cPLA2α (85 kDa, group IVA) plays a major role in the initiation of arachidonic acid metabolism from cell membrane phospholipids.9 The iPLA2 or patatin-like phospholipase domain–containing (PNPLA) family contains 9 enzymes, some of which work as phospholipases and others as lipases, with the Ca2+-independent iPLA2-β (88 to 90 kDa, group VIA-2) being one of the best-studied members.8,10 Lp-PLA2 exhibits unique substrate specificity toward PAF and oxidized phospholipids (oxPLs).11 The sPLA2 family consists of 10 isozymes with low molecular mass that are involved in a number of biological processes, including eicosanoid generation, inflammation, and host defense against bacterial infection.12Arterial inflammation plays a central role in the pathogenesis of atherosclerosis and adverse cardiovascular events. Although cPLA2-α and iPLA2-β are likely to contribute to vascular inflammation and atherosclerosis via the production of various lipid mediators in different cell types,13–16 a wealth of evidence supports a major role for Lp-PLA2 and a subset of sPLA2 isoforms (notably sPLA2-IIA, -III, -V, and -X) in the pathophysiology of atherosclerosis, from initiation and progression to cardiovascular complications. The molecular basis for their unique roles in vascular inflammation and atherosclerosis likely stems from the fact that Lp-PLA2 and sPLA2s have the unique capacity to bind and hydrolyze lipoproteins in distinct and specific manners, thereby producing various lipid mediators and modifying the lipid particles. Notably, Lp-PLA2 and the sPLA2 members are molecularly and biochemically distinct, and thus their roles and underlying mechanisms of action in the blood and within the vascular wall are likely to be different. Low-density lipoprotein (LDL) modified by Lp-PLA2 or sPLA2s acquires potent proatherogenic activities.17,18 In animal studies, enhanced levels of these PLA2s have been related to increased atherosclerosis. In the present review, we outline the biochemical diversity of Lp-PLA2 and sPLA2s and discuss their role in the induction of atherosclerosis-related inflammatory processes, with emphasis on the prognostic value of circulating levels of PLA2 mass or activity as an independent predictor of cardiovascular events. We also discuss the genetic polymorphisms of PLA2s in relation to cardiovascular disease susceptibility and ongoing clinical studies using the newly developed Lp-PLA2 and sPLA2 inhibitors.Structural and Biochemical Features of PLA2sLipoprotein-Associated PLA2Lp-PLA2 is a Ca2+-independent, 45-kDa secreted protein that circulates in plasma in a constitutively active form11 (Table 1). The enzyme is actively secreted by monocyte-derived macrophages, T lymphocytes, and mast cells, and these cells likely contribute the major source of Lp-PLA2 in plasma.21Table 1. Structural and Functional Features of sPLA2s and Lp-PLA2Structural FeaturesEnzymatic PropertiesMolecular Mass, kDaActive SitePE HydrolysisPC HydrolysisPAF HydrolysisoxPL HydrolysisProteoglycan BindingFoam Cell FormationsPLA2-IIA13.9His/Asp++++/−−?†++++sPLA2-III18.3*His/Asp++++−?†−++sPLA2-V13.8His/Asp++++++−?†++++sPLA2-X13.6His/Asp++++++++?†−++Lp-PLA245Ser/Asp/His−−++++++−−PE indicates phosphatidylethanolamine; PC, phosphatidylcholine.sPLA2s and Lp-PLA2 have different molecular masses and different active sites: a His/Asp dyad and a Ser/Asp/His triad, respectively. Phosphatidylcholine and phosphatidylethanolamine are differentially hydrolyzed by sPLA2s.19 Lp-PLA2 and sPLA2-X have unique capacities to hydrolyze PAF.11 Lp-PLA2 hydrolyzes ox-PLs, including phospholipids with esterified F2-isoprostanes and long fatty acyl chain phospholipid hydroperoxides. On the basis of studies with pancreatic and snake venom sPLA2s,20 their activity on oxidized phosphatidylcholine may be weaker than on nonoxidized phosphatidylcholine. sPLA2-IIA and -V, but not sPLA2-III and -X and Lp-PLA2, show high affinity for heparan sulfate proteoglycans.1 LDLs modified by sPLA2-IIA, -V, and -X are efficiently internalized by macrophages to induce the accumulation of cellular cholesterol ester and formation of foam cells.*Molecular mass of the catalytic domain of sPLA2-III.†Detailed analysis of the enzymatic properties of human sPLA2s toward ox-PLs has not been performed.The gene for Lp-PLA2 (PLA2G7) has 12 exons and is located on chromosome 6p21.2-12. Several missense polymorphisms within the coding regions of PLA2G7 have been described. The Val279Phe variant is found in approximately 30% of the Japanese population (3% to 4% homozygosity). The catalytic activity is absent in homozygotes and is significantly decreased in heterozygotes.22,23The vast majority of Lp-PLA2 in normolipidemic subjects is closely associated with LDL, in particular small, dense LDL particles, which explains why it is referred to as lipoprotein-associated PLA2.24 A small proportion of the circulating enzyme activity is also associated with high-density lipoprotein. It has been estimated that only approximately 0.1% of lipoprotein particles are laden with the enzyme. This latter is particularly enriched into lipoprotein(a), an atherogenic lipoprotein particle that appears to be a preferential carrier of oxPLs in human plasma.25–27The crystal structure of Lp-PLA2 has been solved recently.28 The enzyme is more closely related to neutral lipases and serine esterases than other PLA2s. As a result, the enzyme also exhibits PLA1 and lipase activities.29 Unlike other PLA2s that have a serine/aspartate dyad at the active site and must bind to the water-lipid interface for optimal enzymatic activity, Lp-PLA2 contains a serine/aspartate/histidine catalytic triad and catalyzes the hydrolysis of its various substrates essentially from the aqueous phase.28Lp-PLA2 was discovered because of its ability to catalyze the hydrolysis of PAF and thus was originally named PAF-acetylhydrolase. Besides PAF, the enzyme has a broad specificity for polar phospholipids and hydrolyzes several types of short-chain and oxPLs. Esterified isoprostanes and oxPLs appear as major physiological substrates that can be hydrolyzed both in vitro and in vivo.11,30,31 This suggests a major specific role of Lp-PLA2 in the depletion of oxPLs from lipoproteins. Alternatively, Lp-PLA2 is involved in the production of lysophosphatidylcholine and oxidized nonesterified fatty acids, which are proinflammatory and proapoptotic lipid mediators.32Secreted PLA2sMembers of the sPLA2 family are proteins of low molecular masses (typically 14 to 19 kDa; Table 1), soluble in water, compact, and disulfide-rich.12 Although the different mammalian sPLA2s share a common Ca2+-dependent catalytic mechanism that involves a His-Asp catalytic dyad, they are not functional isoforms and differ by their structural features, enzymatic properties, and tissue and cellular distribution, as well as by gene regulation. Furthermore, they share no sequence homology with Lp-PLA2. These distinct features support the view that these enzymes exert nonredundant roles in atherosclerosis (see below).sPLA2 genes are located in different chromosomes, and 6 of them occur as a gene cluster, yet with independent promoters.33,34 Interestingly, mouse and human genes for sPLA2-IIA and -V are clustered in a syntenic region, which is an atherosclerosis-susceptible locus in LDL-receptor (LDLr) –deficient mice and is a candidate susceptibility locus in humans.35 However, several mouse strains, including the C57BL/6 mouse strain, are naturally deficient in sPLA2-IIA owing to a frameshift mutation in exon 3.36Expression of sPLA2-IIA, and to a lesser extent that of sPLA2-V, is markedly increased by proinflammatory stimuli and is downregulated by antiinflammatory cytokines and glucocorticoids in a variety of cells and tissues.37,38 In humans, sPLA2-V is distributed in different tissues, with highest expression in the heart.39 Human sPLA2-III is detected in the kidney, heart, liver, and skeletal muscle.40 sPLA2-X is constitutively expressed in several immune and digestive organs, as well as in the testis.41,42Human sPLA2-IIA and V are highly basic proteins (pI >8.5) and bind to heparan sulfate proteoglycans in the extracellular matrix of cells and tissues. Conversely, human sPLA2-X and the catalytically active domain of human sPLA2-III are highly acidic (pI <5.3) and do not bind heparan sulfates. sPLA2-X, but not sPLA2-IIA or -V, also exhibits a short N-terminal propeptide that controls its enzymatic activity.12 The central catalytically active domain of human sPLA2-III is in fact flanked by large N- and C-terminal regions that may function as prodomains.In contrast to Lp-PLA2, all sPLA2s must bind tightly to the lipid-water interface to hydrolyze their aggregated phospholipid substrate. sPLA2s thus exhibit an interfacial binding surface of approximately 15 amino acids, which is distinct from the active site and essential for efficient adsorption to phospholipids. sPLA2-III, -V, and -X, but not sPLA2-IIA, contain a tryptophan in their interfacial binding domain that plays a major role in binding and hydrolysis of pure phosphatidylcholine vesicles and phosphatidylcholine-rich substrates such as the cellular plasma membrane and lipoproteins.12,19Proatherogenic Biological Activities of PLA2sIt is generally acknowledged that PLA2s participate in inflammatory reactions through the generation of multiple lipid mediators, including lysophospholipids and free fatty acids, among which arachidonic acid triggers a metabolic cascade that leads to the synthesis of another set of bioactive lipid mediators, including thromboxanes, and leukotrienes.Lipoprotein-Associated PLA2The biological role of Lp-PLA2 has been controversial, with contradictory antiatherogenic and proatherogenic functions. The antiatherogenic properties of Lp-PLA2 were first suggested because of the enzymatic catabolism of biologically active oxPLs in LDL and degradation of PAF.43 Interestingly, mildly oxidized LDL and other apolipoprotein B (apoB)–containing lipoproteins depleted of Lp-PLA2 activity exhibit increased stimulation of monocyte chemotaxis and adhesion compared with Lp-PLA2–nondepleted lipoproteins.44 As more recent studies have ascribed antiinflammatory properties to oxPLs,45 it has been suggested that hydrolysis of oxPLs by Lp-PLA2 might promote inflammation. However, oxPLs appear to function as a negative feedback mechanism to specifically blunt lipopolysaccharide-induced inflammatory responses in severe Gram-negative bacterial infection, although they are potent activators of vascular inflammation in other settings.46 The most compelling basic evidence in favor of an atherogenic role of Lp-PLA2 comes from the observation that hydrolysis of oxPLs by the enzyme generates lysophosphatidylcholine and oxidized free fatty acids, which both exhibit a number of proatherogenic effects.47 Lysophosphatidylcholine, a regulator of the G-protein—coupled receptor G2A, is capable of modulating macrophage and T-cell migration, neutrophil and macrophage activation,48 and phagocytic clearance of apoptotic cells.49 These lysophosphatidylcholine effects may contribute to the initiation and progression of atherosclerosis (Figure).Download figureDownload PowerPointFigure. Schematic representation of proatherogenic pathways induced by sPLA2s or Lp-PLA2. Several sPLA2 enzymes have been shown to promote the modification of LDLs, enhancing their binding to matrix proteoglycans and facilitating their aggregation and oxidation. Both sPLA2 and Lp-PLA2 activities lead to the generation of bioactive fatty acids and lysophosphatidylcholine, thereby promoting cell activation and production of inflammatory cytokines. sPLA2s, but not Lp-PLA2, also promote macrophage foam cell formation by modifying lipoprotein particles. Lp-PLA2 is strongly expressed within the necrotic core and surrounding macrophages of vulnerable and ruptured plaques in humans and is thought to promote apoptotic cell death. Excess production of lysophosphatidylcholine (Lyso-PC) in response to PLA2 activation may inhibit apoptotic cell clearance, thereby perpetuating vascular inflammation and promoting necrotic core formation. Ox-LDL indicates oxidized LDL.Secreted PLA2sAs described below, multiple functions of sPLA2s may account for their proatherogenic effects (Figure).sPLA2-Induced Production of Proinflammatory MediatorssPLA2s promote the production of proinflammatory mediators via their catalytic activity. Hydrolysis of phosphatidylcholine in LDL by sPLA2-IIF, -III, -V, and -X produces large amounts of unsaturated fatty acids and lysophosphatidylcholine.50,51 It is noteworthy that although sPLA2-IIA exerts very potent enzymatic activities in anionic phospholipids, it very modestly hydrolyzes LDL and is also virtually inactive in phosphatidylcholine-rich substrates such as the extracellular membranes of resting cells.12,51,52 However, because sPLA2-IIA is likely the most abundant isoform present in human serum and within the arterial wall, its high local concentration may somehow compensate for its low enzymatic activity.A subtle distinguishing feature between sPLA2-V and -X resides in their respective capacity to hydrolyze different phosphatidylcholine species of lipoproteins. sPLA2-X preferentially hydrolyzes phosphatidylcholine species that contain arachidonate and linoleate, whereas sPLA2-V hydrolyzes the linoleates in preference to polyunsaturates.50 This substrate preference appears to be linked to the content of sphingomyelin and phospholipid partitioning in lipoproteins.53,54 Because sPLA2-III, -V, and -X have not been detected in large amounts in serum, their actions in LDL are believed to occur mainly in the intima, where LDL accumulates.sPLA2-Induced LDL ModificationMost sPLA2 isoforms are capable of modifying circulating LDL to form more proatherogenic particles with an increased negative charge. In blood, sPLA2-IIA can hydrolyze LDL, which leads to the formation of smaller and denser LDL particles52 that have been shown to be highly atherogenic. sPLA2-induced lipolysis of LDLs alters the conformation of apoB100 on the LDL particle, enhancing their retention to matrix proteoglycans.52,55 Increased interaction of sPLA2-IIA–modified LDLs with glycosaminoglycans depends on a specific region in apoB100 (site A, residues 3148 to 3158) that becomes functional in sPLA2-modified LDLs.56 The accumulation of LDL in the proteoglycan matrix of the intimal subendothelial space is a key initiating step in atherosclerosis. sPLA2-modified LDLs may also activate endothelial cells. For instance, sPLA2-X–treated LDLs stimulate the expression of adhesion molecules in endothelial cells.57sPLA2-Induced LDL Oxidation and Foam Cell FormationOne major effect of sPLA2 on LDLs is to increase their susceptibility to cell-induced oxidation and foam cell formation. Incubation of LDLs treated with sPLA2-III, -V, or -X with macrophages induces foam cell formation similar to that observed with oxidized LDL.51,57,58 sPLA2-V–modified LDL promotes foam cell formation by a class A macrophage scavenger receptor (SR-A)– and CD36-independent process that likely involves cell-surface proteoglycans59 and sPLA2-induced LDL aggregation.60 Interestingly, macrophages from human sPLA2-IIA transgenic mice increase LDL oxidation,61 and high-density lipoproteins from sPLA2-IIA transgenic mice fail to protect against the cellular effects of LDL oxidation.62 The specific effect of sPLA2-X in macrophages has been examined recently via generation of sPLA2-X–overexpressing macrophages.63 As expected from previous studies, sPLA2-X increased foam cell formation of macrophages incubated with native or oxidized LDL, but surprisingly, macrophage activation and inflammatory responses were inhibited, with reduced cell adhesion and nitric oxide production, decreased tumor necrosis factor-α secretion, and increased interleukin-10 secretion.63 Thus, LDL modification and foam cell formation in response to the various sPLA2 isoforms are likely associated with the induction of distinct macrophage phenotypes.sPLA2 Receptor–Dependent Proinflammatory FunctionsBesides proatherogenic functions associated with their enzymatic activity, sPLA2s may also stimulate inflammatory responses by nonenzymatic mechanisms mediated by binding of sPLA2s to specific membrane receptors, possibly including the M-type receptor.64,65 The M-type receptor is expressed on neutrophils, monocytes, and macrophages, and the mouse receptor binds with high to moderate affinity several sPLA2s, including sPLA2-IIA, -V, and -X.66 Interestingly, both wild-type and catalytically inactive sPLA2s induce the production of cytokines and chemokines in human monocytes/macrophages, which suggests the contribution of a membrane receptor, possibly the M-type receptor.67,68PLA2 Expression in Atherosclerotic LesionsLipoprotein-Associated PLA2Lp-PLA2 messenger RNA and protein were detected in macrophages in both human and rabbit atherosclerotic lesions.69,70 High Lp-PLA2 activity was also detected in atherosclerotic aortas of Watanabe heritable hyperlipidemic rabbits compared with normal aortas from control rabbits.Interestingly, extensive Lp-PLA2 expression was found in human advanced lesions and rupture-prone lesions, the so-called thin-cap fibroatheromas.71 Lp-PLA2 was found within apoptotic macrophages, which suggests that its products either represent a marker of apoptosis or might play a causal role in the induction of cell death. Lysophosphatidylcholine, a major product of Lp-PLA2 activity in oxPLs, potently inhibits apoptotic cell clearance,49 which potentially may explain the preferential localization of Lp-PLA2 in necrotic cores. Only minimal reactivity to Lp-PLA2 was detected in pathological intimal thickening or fibroatheromas, and when present, it was mostly localized to the lipid pool or necrotic core. Minimal expression was found in smooth muscle cells.71 In a prospective cohort study of patients undergoing carotid endarterectomy, expression of Lp-PLA2 and lysophosphatidylcholine was higher in plaques from patients with than those without cardiovascular events,72 which suggests that Lp-PLA2 is part of a causal pathway for plaque vulnerability.Secreted PLA2ssPLA2-IIA has been detected in human carotid atherosclerotic plaques but not in areas of the adjacent normal arterial wall.73,74 Its expression was mainly confined to plaque areas with massive lipid accumulation and leukocyte infiltration, cellular necrosis, and calcifications. sPLA2-V and -X have been detected in human and mouse atherosclerotic lesions.60 sPLA2-III is also highly expressed in the necrotic core and fibrous cap of human plaques.51PLA2s and Experimental AtherosclerosisLipoprotein-Associated PLA2Increasing the activity of Lp-PLA2 by adenoviral gene transfer of human Lp-PLA2 in apolipoprotein E (apoE)−/− mice reduced atherosclerosis and macrophage accumulation.75,76 The reduction of atherosclerotic lesions was more pronounced in male than in female mice and paralleled the level of Lp-PLA2 activity after gene transfer.77In a model of postangioplasty restenosis in cholesterol-fed rabbits, adenovirus-mediated Lp-PLA2 gene transfer reduced neointima formation in aorta.78 These studies were suggestive of an atheroprotective role of Lp-PLA2 in mice. However, Lp-PLA2 circulates largely bound to high-density lipoprotein in the mouse, whereas it is bound to LDL in humans. Experiments in mice are therefore not very informative on the role of Lp-PLA2 in humans. Interestingly, a recent report by De Keyzer et al demonstrated for the first time an association between blood levels of oxidized LDL and Lp-PLA2 activity in hypercholesterolemic minipigs.79 This association was further supported by the observation that oxidized LDL induced Lp-PLA2 gene expression in human blood–derived macrophages. The increase in Lp-PLA2 activity was also associated with an increase in lysophosphatidylcholine, increased expression of proinflammatory genes in coronary plaque macrophages, and progression of atherosclerosis. This is indirect evidence that Lp-PLA2 is proatherogenic in large-animal models of atherosclerosis.Secreted PLA2sBecause C57BL/6 mice have a natural null mutation in the sPLA2-IIA gene, transgenic C57BL/6 mice overexpressing the human sPLA2-IIA gene (sPLA2-IIA Tg) have been generated to evaluate the effect of this sPLA2 isoform in murine models of atherosclerosis. Given a high-fat diet, these mice showed increased susceptibility to atherosclerosis, with increased fatty streak lesions in their aortic sinus compared with their nontransgenic littermates.80 Similar findings were reported in a model of bone marrow transplantation in irradiated LDLr−/− mice. LDLr−/− mice transplanted with bone marrow from sPLA2-IIA Tg animals or transgenic mice overexpressing human sPLA2-IIA in macrophages and maintained on a cholesterol-rich diet developed larger lesions in the aortic arch and aortic sinus than animals transplanted with wild-type bone marrow.81,82Transplantation of bone marrow–derived cells that overexpressed sPLA2-V in LDLr−/− mice also increased atherosclerotic lesion area, which was associated with increased lesional collagen deposition.83 Moreover, sPLA2-V deficiency in bone marrow–derived cells caused a reduction in atherosclerotic lesion area in the aortic arch and thoracic aorta in LDLr−/− mice. However, the reduction in lesion area was not seen in apoE−/− mice lacking sPLA2-V, despite reduced collagen deposition in these mice.84 In these studies, sPLA2-V did not alter foam cell formation in response to LDL from apoE−/− mice, whereas hydrolysis of LDL from LDLr−/− mice was a prerequisite for this process. These results suggest that the proatherogenic properties of sPLA2-V may depend in large part on its ability to enhance the proatherogenic potential of LDL.84 Although sPLA2-X is the most efficient sPLA2 to hydrolyze LDL and high-density lipoproteins51 and to promote foam cell formation,57 no direct evidence for a role of this isoform in atherosclerosis is currently available.Experimental Pharmacological Intervention With Selective Inhibitors of Lp-PLA2 and sPLA2sAdditional evidence for the direct involvement of Lp-PLA2 and sPLA2s in atherosclerosis was recently provided by studies that showed that pharmacological inhibition of these enzymes is effective in treating atherosclerosis in several animal models. Darapladib, under development by GlaxoSmithKline, is a selective inhibitor of Lp-PLA2.85 Varespladib (A-002, from Anthera Pharmaceuticals) inhibits sPLA2-IIA, -V, and -X with high affinity86 but has no affinity for sPLA2-III.87Lp-PLA2 InhibitionIn a model of diabetic/hypercholesterolemic swine, treatment with darapladib markedly inhibited plasma and lesion Lp-PLA2 activity, reduced the lysophosphatidylcholine content of lesions, and attenuated the development of atherosclerosis in coronary arteries. Analysis of coronary gene expression showed that darapladib exerted a general antiinflammatory action. The necrotic core area was significantly smaller in treated animals. Furthermore, the decreased macrophage content in the treated animals was associated with downregulation of gene expression, the majority of which was responsible for macrophage and T-lymphocyte recruitment and functioning. Selective inhibition of Lp-PLA2 activity appears to decouple the primary effect of hypercholesterolemia from the resulting inflammatory-immune effect, which results in more stable lesions.88sPLA2 InhibitionVarespladib has been shown to significantly reduce atherosclerosis by 40% to 75% in apoE−/− mice fed a high-fat diet89,90 and to attenuate the development of angiotensin II–induced aortic aneurysms.89 However, in 1 of the 2 studies in apoE−/− mice,89 plasma total cholesterol was also decreased, which may contribute to the atheroprotective effect of varespladib. Interestingly, in the PLASMA (Phospholipase Levels And Serological Markers of Atherosclerosis) phase II study, a reduction of cholesterol levels was also observed in patients with coronary artery disease (CAD) treated with varespladib.91 In a guinea pig model in which sPLA2-IIA and other isoforms are expressed, treatment with varespladib did not change plasma cholesterol levels but reduced aortic lipid accumulation.90 The fact that varespladib exerts an antiatherogenic effect in C57BL/6 apoE−/− mice that do not express sPLA2-IIA suggests that sPLA2-V, sPLA2-X, or both contribute to atherosclerosis and are targeted in vivo by this inhibitor.Lp-PLA2 and sPLA2 as Biomarkers of Cardiovascular Risk: Epidemiological EvidenceLp-PLA2 in Apparently Healthy IndividualsInterest in Lp-PLA2 as a biomarker for cardiovascular diseases emerged after the publication of a report from WOSCOPS (West of Scotland Coronary Prevention Study) that showed a positive association between elevated circulating concentrations of Lp-PLA2 and risk of coronary events in hypercholesterolemic men.92 This finding was important because it could not be predicted from previous scientific background on Lp-PLA2 (ie, before publication of the studies that used darapladib) and because of its potential implications with regard to the biology of CAD. The other important finding from WOSCOPS was that the positive association between elevated Lp-PLA2 levels and coronary risk was not confounded by classic cardiovascular risk factors, in contrast to other tested inflammatory biomarkers, including white cell count, C-reactive protein (CRP), and fibrinogen.92 These results suggested that measurement of Lp-PLA2 mass could improve cardiovascular risk assessment and led to the idea that inhibition of Lp-PLA2 activity might constitute an independent therapeutic target separate from lipid-lowering and other antiinflammatory therapies.However, these results were not systematically confirmed in all subsequent studies (Table 2). Studies that included a lower number of cases than the index WOSCOPS generally confirmed the positive association between elevated levels of Lp-PLA2 and future risk of cardiovascular disease. The most cited among these reports have included data from the MONICA (MONItoring of trends and determinants in CArdiovascular disease)-Augsburg cohort93 or the Rotterdam,94 Rancho Bernardo,95 or Bruneck96 studies. Other studies were not able to confirm the increased risk of incident coronary heart disease associated with elevated levels of Lp-PLA2, including the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) trial, the Women's Health Study,97 and a population-based cohort study from Malmö, Sweden. In the Atherosclerosis Risk In Communiti" @default.
• W2085453879 created "2016-06-24" @default.
• W2085453879 creator A5061562246 @default.
• W2085453879 creator A5082931018 @default.
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• W2085453879 date "2010-11-23" @default.
• W2085453879 modified "2023-10-15" @default.
• W2085453879 title "Lipoprotein-Associated and Secreted Phospholipases A ₂ in Cardiovascular Disease" @default.
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